Darunavir and Atazanavir Have Similar Modest Impact on Insulin Sensitivity

53rd ICAAC, September 10-13, 2013, Denver

Mark Mascolini

Darunavir/ritonavir and atazanavir/ritonavir, both taken once daily, had a similar modest impact on insulin sensitivity in a phase 4 substudy involving 27 adults starting their first antiretroviral regimen [1]. HOMA-IR and estimated HOMA-beta rose slightly with darunavir/ritonavir but not with atazanavir/ritonavir.

Protease inhibitor (PI) therapy has long been linked to insulin resistance, incident diabetes, and cardiovascular disease. Compared with older PIs, atazanavir has a good metabolic profile. To compare atazanavir with another newer PI, darunavir, researchers planned the METABOLIK study. This phase 4 trial randomized 65 antiretroviral-naive adults to once-daily darunavir/ritonavir or atazanavir/ritonavir, both with tenofovir/emtricitabine [2]. A week-48 analysis discerned no clinically relevant differences between arms for changes in lipids, glucose, or insulin sensitivity.

This insulin sensitivity subanalysis involved 14 men who took darunavir/ritonavir and 13 men who took atazanavir/ritonavir. Median age stood at 29 in the darunavir group and 26 in the atazanavir group. Proportions of blacks and whites were 57% and 43% for darunavir and 62% and 31% for atazanavir. Median body mass index stood at 24.1 kg/m2 in the darunavir group and 23.4 kg/m2 in the atazanavir group. Respective median CD4 counts were 234 and 271, while average viral loads were 5.11 and 4.77 log10 copies/mL (about 129,000 and 58,900 copies).

Two of 14 men randomized to darunavir discontinued before week 48, as did 3 of 12 randomized to atazanavir. An adverse event accounted for 1 of the 3 dropouts in the atazanavir arm.

Euglycemic hyperinsulinemic clamp analysis determined that glucose disposal improved slightly in both treatment arms by week 48. Insulin sensitivity increased modestly in both arms through study week 12 then returned to baseline by week 48. Insulin resistance calculated by HOMA-IR lay well below 6.0 at both week 12 and week 48 with both drugs. (A value at or above 6 indicates insulin resistance.) A HOMA-beta analysis determined that beta-cell function rose slightly at week 12 and week 48 with darunavir but remained unchanged with atazanavir.

At study week 48 median brachial artery reactivity (indicating endothelial function) increased 1.84% above baseline with darunavir and fell 2.81% with atazanavir. Percentages of study participants with fasting lipid abnormalities were similar for darunavir and atazanavir: triglycerides at or above 150 mg/dL (50% and 46%), total cholesterol at or above 200 mg/dL (14% and 8%), low-density lipoprotein cholesterol at or above 130 mg/dL (14% and 15%), and high-density lipoprotein cholesterol at or below 40 mg/dL (50% and 46%).

Expected differences in bilirubin levels between darunavir and atazanavir were the only clinically relevant differences in safety parameters measured.

The researchers concluded that darunavir/ritonavir and atazanavir/ritonavir have similar insulin resistance and endothelial function profiles.

Virologic response rates were less than stellar for both darunavir/ritonavir and atazanavir/ritonavir started by antiretroviral-naive patients. Seven of 13 people (54%) randomized to atazanavir and 11 of 14 (78%) randomized to darunavir/ritonavir had a week-48 viral load below 50 copies. The low number of participants in the subanalysis makes these response rates less surprising. At week 48 in the 65-person overall trial, 76.5% of participants randomized to darunavir/ritonavir and 71% randomized to atazanavir/ritonavir had a viral load below 50 copies [2].